Herpes viruses inflict a wide range of diseases against humans and animals. For instance; herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the Epstein-Barr virus (EBV) causes infectious mononucleosis.
Over the past two decades, a class of compounds known as the purine and pyrimidine nucleoside analogs has been the subject of much attention by investigators in the search for new therapeutic agents for the treatment of herpes virus infections. As a result, several nucleoside analogs have been developed as antiviral agents. The most successful to date is acyclovir which is the agent of choice for treating genital herpes simplex infections. Other nucleoside analogs which are used therapeutically for the treatment of herpes infections include vidarabrine, idoxuridine, trifluridine and ganciclovir.
The mode of action by which the nucleoside analogs exert their antiviral effect is thought to involve the inhibition of viral nucleic acid replication. In the case of herpes viruses, the production of new viral deoxyribonucleic acid (DNA), an essential stage of viral replication, depends on the interaction of the virally encoded enzyme, DNA polymerase, with cellular deoxynucleotides. The nucleoside analog, when converted enzymatically in vivo to its triphosphate derivative, acts as an alternate substrate (i.e. a "fraudulent substrate) for the viral DNA polymerase, and becomes incorporated into the growing viral DNA chain. Since the nucleoside analog either lacks and essential group, e.g. the 3'-hydroxyl, or has the wrong stereochemistry, it also acts as a "chain terminator" of the growing viral DNA chain. The net effect is that the nucleoside analog acts in vivo as an inhibitor of the viral DNA polymerase.
Although the therapeutically useful nucleoside analogs have proven to be a valuable agents for combatting or controlling herpes infections, the agents are not without side effects. For example, skin rashes and renal impairment have been reported as side effects for acyclovir (see Physicians' Desk Reference, 44th ed., Medical Economics Inc., Oradell, N.J., USA, 1990, pp 819-821). For a recent review of the available antiviral drugs and their side effects, see M. C. Nahata, "Antiviral Drugs: Pharmacokinetics, Adverse Effects, and Therapeutic Use", J. Pharm. Technol., 3, 100 (1987). Hence, safety as well as cost advantages would be realized if these agents were formulated in a manner which enhanced their therapeutic activity.
We now have found that the antiviral activity of the nucleoside analogs can be enhanced synergistically, without concomitant enhancement of toxic effects, by combining the same with certain peptide derivatives having selective herpes ribonucleotide reductase inhibiting properties.
Ribonucleotide reductase (RR) is the enzyme responsible for the conversion of ribonucleotides to deoxyribonucleotides. The role of RR in DNA biosynthesis has been reviewed recently by J. Stubbe, J. Biol. Chem. 265, 5329 (1990).
In 1985, T. Spector et al., Proc. Natl. Acad. Sci. USA, 82, 4254 (1985) reported that a combination of acyclovir and a semicarbazone RR inhibitor, 2-acetylpyridine thiosemicarbazone, produced a synergistic antiherpes effect. However, the combination of acyclovir with the RR inhibitor hydroxyurea was toxic to the host cell and acyclovir combined with some related semicarbazone derivatives did not always potentiate the antiherpes activity of acyclovir.
A three-way combination of acyclovir, bacitracin and an RR inhibiting nonapeptide has been reported by E. A. Cohen et al., U.S. Pat. No. 4,795,740, Jan. 3, 1989. Curiously, the antiherpes activity of the latter combination was indicated as being equal or less than acyclovir alone.
Still other synergistic combinations containing a nucleoside analog as a component have been reported; for example:
T. P. Zimmerman and G. Wolberg, European patent application 235931, published Sep. 9, 1987 (nucleoside analogs plus nucleoside transport inhibitors);
K. O. Smith, Canadian patent 1,239,093, issued Jul. 12, 1988 (nucleoside analog plus an interferon);
T. Spector et al., Proc. Natl. Acad. Sci. USA, 86, 1051 (1989), (nucleoside analog plus RR inhibitor);
T. Spector et al., U.S. Pat. No. 4,758,572, issued Jul. 19, 1988 (nucleoside analogs plus RR inhibitors); and
T. A. Blumenkopf et al, European patent application 349,243, published Jan. 3, 1990 (nucleoside analogs plus RR inhibitors).
The combination of the present invention can be distinguished from the preceding combinations by its different composition and/or its relative lack of toxicity.